Summary Of Exposure |
A) USES: Olanzapine is an atypical antipsychotic. It is used for the treatment of schizophrenia and rapid sedation of patients with undifferentiated agitation. It is also used to treat patients with bipolar I disorder.
B) PHARMACOLOGY: Olanzapine is a dopamine, serotonin, muscarinic, and histamine receptor antagonist.
C) TOXICOLOGY: Toxicity is an extension of the pharmacology. In overdose, olanzapine also acts as an alpha-adrenergic receptor antagonist and may cause hypotension.
D) EPIDEMIOLOGY: Exposures to olanzapine are common. Most patients have mild to moderate sedation, but some patients will require life support. Deaths are rare from single-substance ingestions.
E) WITH THERAPEUTIC USE
1) Nausea, vomiting, dry mouth, constipation, dyspepsia, sedation, dizziness, tachycardia, orthostatic hypotension, elevated liver enzymes, arthralgia, extremity pain, elevated serum CPK, anticholinergic effects, orthostasis, agitation, insomnia, nervousness, constipation, and dry mouth have been reported with therapeutic use. Long-term use may cause weight gain and glucose intolerance. In the postmarketing period, there have been rare reports of hepatitis and cholestatic or mixed liver injury. Neuroleptic malignant syndrome (NMS), due to dopaminergic blockade, associated with olanzapine therapy has been reported, but is rare.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Somnolence, ataxia, extrapyramidal effects, tachycardia, miosis, and nystagmus have been reported.
2) SEVERE TOXICITY: Seizures, delirium, coma, respiratory depression, hypotension, oculogyric crisis, and central diabetes insipidus have been reported. The most common effects are CNS depression, which may progress to coma or delirium, and hypotension.
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Vital Signs |
3.3.2) RESPIRATIONS
A) WITH POISONING/EXPOSURE 1) Decreased respirations are notable following overdoses (Fogel & Diaz, 1998; O'Malley et al, 1998). An overdose of 1110 mg resulted in tachypnea (respiratory rate, 28 breaths/minute) in 1 adult (Gardner et al, 1999).
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) Elevated body temperature has been reported following therapeutic use (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007).
B) WITH POISONING/EXPOSURE 1) CASE REPORT: A 17-month-old toddler (weight: 12.8 kg) developed lethargy, drowsiness, extrapyramidal symptoms, and fever (38 to 39 degrees C for 3 days) after ingesting 2 to 5 olanzapine 10 mg tablets. Her symptoms gradually improved following supportive care and she was discharged on day 7 (Tanoshima et al, 2013).
2) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
3.3.4) BLOOD PRESSURE
A) WITH THERAPEUTIC USE 1) Orthostatic hypotension has been observed in greater than 5% of patients given olanzapine (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007).
3.3.5) PULSE
A) WITH THERAPEUTIC USE 1) A mean increase in heart rate of 2.4 beats per minute has been reported in clinical trials with tachycardia occurring in greater than 5% of the patients. It is possible that this effect is associated with orthostatic hypotensive changes (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Bronson & Lindenmayer, 2000).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Esotropia with diplopia and headaches have been reported following olanzapine and fluoxetine therapy. When olanzapine was discontinued, symptoms cleared within 1 week (Singh et al, 2000).
B) WITH POISONING/EXPOSURE 1) Overdoses have resulted in unreactive, persistent, pinpoint pupils (alpha-adrenergic effect), (Shrestha et al, 2001; Fogel & Diaz, 1998; O'Malley et al, 1998) which resembles an opiate or alpha-2 agonist overdose, but were unresponsive to naloxone (O'Malley et al, 1999; O'Malley et al, 1998). Nystagmus and oculogyric crisis have been reported following an overdose (Davis et al, 2005; Shrestha et al, 2001; Chambers et al, 1998).
2) In a retrospective analysis of 26 patients with olanzapine poisoning (doses ranged from 30 mg to 840 mg), 8 patients had marked miosis (Palenzona et al, 2004).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Small reductions in orthostatic blood pressure have been reported in olanzapine-treated patients during clinical trials (Beasley et al, 1996; Beasley et al, 1996a).
b) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Two patients (2%) developed hypotension (systolic BP less than 100 mmHg) with suspected causal relation to olanzapine (dose used: 60 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) Alpha adrenergic blockade (alpha-1 greater than alpha-2) may lead to hypotension and tachycardia following overdoses. Overdoses have resulted in hypotension (Chambers et al, 1998).
b) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
c) CASE REPORT: A 28-month-old girl inadvertently ingested 30 mg of olanzapine and was found unconscious within 6 hours of ingestion. Tachycardia and hypertension were noted upon arrival. She subsequently became hypotensive and was admitted to the pediatric ICU with supportive therapy. Six hours after admission she spontaneously regained consciousness. Thirty-six hours after admission she had full recovery (Lankheet et al, 2011).
d) CASE REPORT: A 48-year-old woman developed orthostatic hypotension approximately 2 hours after ingesting 200 mg olanzapine. The orthostasis resolved 24 hours later (Dougherty et al, 1997).
e) CASE REPORT: Blood pressure of 96/64 mmHg has been reported in a 55-year-old woman following the ingestion of greater than 1 gram of olanzapine (O'Malley et al, 1998).
B) TACHYARRHYTHMIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
b) CASE REPORT : Narrow complex sinus tachycardia on ECG (heart rate 146, PR 124 msecs, QRS 76 msecs, QT 276 msecs, R axis 97, and nonspecific ST and T wave abnormality) was reported following ingestion of up to 600 mg of olanzapine in a 31-year-old woman (Fogel & Diaz, 1998).
c) CASE REPORT: Ventricular tachycardia, followed by a brief period of asystole before returning to sinus rhythm, occurred in a 62-year-old man several hours after intentionally ingesting 50 olanzapine 15 mg tablets. Brief periods of atrial fibrillation were also noted on the ECG for several days postingestion (Davis et al, 2005).
d) CASE REPORT: A 21-year-old woman with no previous history of dysrhythmias presented with nausea, dizziness, and vomiting approximately 1 hour after ingesting 14 olanzapine tables (10 mg each). An initial ECG revealed normal sinus rhythm; however, she developed atrial fibrillation (with large fibrillatory waves and normal ventricular rate) 4 hours later. After 10 minutes, the ECG normalized spontaneously (Yaylaci et al, 2011).
C) PROLONGED QT INTERVAL 1) WITH THERAPEUTIC USE a) Unlike other antipsychotic medications, olanzapine does not contribute significantly to QTc prolongation that could result in potentially severe ventricular dysrhythmias, due to its mechanism of action (Czekalla et al, 2001; Isbister et al, 2001). However, QTc prolongation has been reported (Petersen et al, 2014).
b) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. One patient developed QTc prolongation (510 ms) with suspected causal relation to olanzapine (doses used: 90 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Tachycardia (160 beats per minute) and QTc prolongation of 0.423 seconds (normal less than 0.4 seconds) were observed in a 58-year-old woman found unconscious following an overdose of 560 mg. Following supportive care the patient was hemodynamically stable within 10 hours (Ballesteros et al, 2007).
D) TACHYCARDIA 1) WITH THERAPEUTIC USE a) Tachycardia occurred in greater than 5% of patients in clinical trials, with an overall mean increase in heart rate of 2.4 beats/minute (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007). Chest pain has also been reported in clinical trials.
b) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Two patients (2%) developed tachycardia (heart rate greater than 100 beats/min) with suspected causal relation to olanzapine (doses used: 45 to 90 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) Tachycardia and chest pain, without dysrhythmia, may occur following an overdose (related to antimuscarinic activity) (Ballesteros et al, 2007; Isbister et al, 2001; Cohen et al, 1999; Gardner et al, 1999).
b) CASE REPORT: Tachycardia (160 beats per minute) and QTc prolongation of 0.423 seconds (normal less than 0.4 seconds) were observed in a 58-year-old woman found unconscious following an overdose of 560 mg. Following supportive care the patient was hemodynamically stable within 10 hours (Ballesteros et al, 2007).
c) CASE REPORT: A 4-year-old boy with a history of an untreated seizure disorder developed tachycardia (170 beats/min) and agitation, followed by somnolence and minimal response to painful stimuli after ingesting an unknown quantity of olanzapine. He was treated with 20% lipid emulsion (a 1.5 mL/kg lipid emulsion bolus, followed by a 0.25 mL/kg/min infusion) starting approximately 90 minutes after presentation. His heart rate decreased to 115 to 120 beats/min within 15 minutes of the initial bolus and he became more arousable. During the transfer to the ICU, the lipid emulsion infusion was inadvertently discontinued for 45 minutes and his heart rate increased to 180 to 190 beats/min. Once again, the patient was treated with an additional lipid emulsion bolus of 1.5 mL/kg, followed by the lipid infusion. He gradually recovered and was discharged 2 days later (McAllister et al, 2011).
d) CASE SERIES: Sinus tachycardia occurred in 3 adult patients following olanzapine overdose. One patient had ingested 200 mg of olanzapine and the other 2 patients had ingested unknown amounts. All 3 patients recovered following supportive care (Dougherty et al, 1997).
e) CASE REPORT: A 28-month-old girl inadvertently ingested 30 mg of olanzapine and was found unconscious within 6 hours of ingestion. Tachycardia of 130 beats per minute and hypertension were noted upon arrival. She subsequently became hypotensive and was admitted to the pediatric ICU with supportive therapy. Six hours after admission she spontaneously regained consciousness. Thirty-six hours after admission she had full recovery (Lankheet et al, 2011).
f) CASE REPORT: Tachycardia (heart rate, 140 beats/minute) has been reported in a 31-year-old woman following an overdose of up to 600 mg olanzapine(Fogel & Diaz, 1998).
E) CARDIAC ARREST 1) WITH POISONING/EXPOSURE a) Following 2 deaths attributed to olanzapine overdose (no other drug overdose), no significant pathologic findings were reported with the exception of moderate coronary artery disease in 1 patient. The authors speculate that overdose may result in cardiac toxicity at the cellular membrane level, although further work will need to be completed to elucidate the exact mechanism of death following overdose (Gerber & Cawthon, 2000). Significant dysrhythmias have not been observed after overdose to date.
F) HYPERTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 28-month-old girl inadvertently ingested 30 mg of olanzapine and was found unconscious within 6 hours of ingestion. Tachycardia and hypertension were noted upon arrival. She subsequently became hypotensive and was admitted to the pediatric ICU with supportive therapy. Six hours after admission she spontaneously regained consciousness. Thirty-six hours after admission she had full recovery (Lankheet et al, 2011).
b) A 14-year-old girl and a 17-year-old boy developed transient hypertension after olanzapine overdose (blood pressure 150/90 mmHg in the girl and from 145/80 to 210/110 in the boy) (Theisen et al, 2005).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DECREASED RESPIRATORY FUNCTION 1) WITH THERAPEUTIC USE a) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. One patient developed respiratory distress with suspected causal relation to olanzapine (doses used: 50 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) Decreased respirations and CNS depression have been reported following overdoses. Protected airway and intubation may be required in these patients (Tse et al, 2008; Theisen et al, 2005; O'Malley et al, 1999; Fogel & Diaz, 1998).
B) PULMONARY EMBOLISM 1) WITH THERAPEUTIC USE a) CASE REPORTS: Six case reports have been published showing a possible association between olanzapine and development of pulmonary embolism. One patient, a 47-year-old schizophrenic woman who was taking lithium and olanzapine, was found dead in her home. The internal examination of the patient revealed an acute pulmonary embolus within the left main pulmonary artery with extension into the lobar branches. An adherent thrombus within the left popliteal vein was observed after the dissection of the leg vessels. Of the 6 cases, only 2 patients had known risk factors for the development of a pulmonary embolus (obesity and a recent ankle fracture) (Kannan & Molina, 2008).
b) CASE REPORT: Pulmonary embolism occurred in a 28-year-old man after beginning olanzapine therapy for the treatment of a psychotic disorder. Olanzapine therapy was initiated at 10 mg/day and gradually increased to 30 mg/day. Following 10 weeks of therapy, a pulmonary embolism was found on spiral CT, which was performed after the patient complained of respiratory pain and experienced 2 episodes of hemoptysis. Olanzapine treatment was discontinued and the patient's symptoms resolved with anticoagulant therapy. Because tests for possible coagulation disorders did not reveal any underlying risks factors for this patient, olanzapine was believed to be the causal effect for the development of the pulmonary embolism (Waage & Gedde-Dahl, 2003).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM DEPRESSION 1) WITH THERAPEUTIC USE a) Olanzapine has been shown to have acute central nervous system depressant effects in humans during clinical trials. Dose-related somnolence is the most frequent adverse effect, occurring at an incidence of 26%, and appears to be dose-related. Asthenia and dizziness have occurred in 10% and 8% to 15% of patients, respectively, in clinical trials (Beasley et al, 1996). b) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Twenty-three patients (25%) developed CNS depression with suspected causal relation to olanzapine (doses used: 45 to 120 mg) (Petersen et al, 2014). c) Post-injection olanzapine delirium/sedation syndrome (PDSS) has been reported in several patients after receiving olanzapine long-acting IM injection (OLAI). Symptoms of PDSS are similar to those of acute oral olanzapine overdose. It is suggested that PDSS may occur after an accidental intravascular entry of olanzapine from a vessel injury during the injection. In addition, olanzapine pamoate salt dissolves more rapidly in blood than in muscle tissue, resulting in the rapid rate of drug release and very high olanzapine concentrations. Patients with low BMI and/or higher age may have a higher risk in developing PDSS (Lukasik-Glebocka et al, 2015). 1) CASE REPORT: Post-injection olanzapine delirium/sedation syndrome (PDSS) developed in a 60-year-old schizophrenic woman (BMI 18.2 kg/m[2]) 10 minutes after receiving her fourth IM injection of olanzapine pamoate (dose, 405 mg every 4 weeks). She presented unconscious with bilateral miosis, occasional agitation, and slight rigidity. Vital signs included a blood pressure of 140/75 mmHg, heart rate of 112 to 130 beats/min, and a respiratory rate of 16 breaths/min. Her body temperature also increased from 36.6 degrees C to 38.2 degrees C during the first 5 hours. Following supportive care, including treatment with midazolam for agitation and biperiden for rigidity, her symptoms gradually improved and she was fully conscious 48 hours after the injection. Laboratory results revealed serum olanzapine concentrations of 698, 530, 544, and 271 ng/mL at 5, 14, 24, and 48 hours after injection (recommended therapeutic concentration: 20 to 80 ng/mL), respectively (Lukasik-Glebocka et al, 2015).
2) WITH POISONING/EXPOSURE a) Overdoses have resulted in profound CNS depression (antihistaminic effect) (Lankheet et al, 2011; Ramos et al, 2008; Tse et al, 2008; Ballesteros et al, 2007; Isbister et al, 2001; Shrestha et al, 2001; Bosch et al, 2000; Cohen et al, 1999; O'Malley et al, 1999) . Overdoses may result in delirium, or impaired judgement, thinking, or motor skills (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Ferraro et al, 2001; Cohen et al, 1999) . b) ONSET 1) Significant CNS depression (ie, no response to painful stimuli) developed within 40 minutes of an intentional olanzapine ingestion in 2 adults. One patient had ingested 600 to 700 mg of olanzapine, diazepam 20 mg, and propranolol 960 mg, while the other patient ingested an unknown quantity of olanzapine and lithium (serum concentration was subtherapeutic) and citalopram 80 mg. Serum concentrations (greater than 2500 mcg/L on admission) were elevated in both patients and remained increased for several days. Both patients required intubation and mechanical ventilation with a gradual improvement in neurologic function over a period of at least 80 hours. Each recovered completely with no neurologic deficits (Tse et al, 2008).
2) Profound CNS depression was reported in 31-year-old woman within 2 hours after ingestion of 800 mg olanzapine. Following decontamination and supportive care, the patient recovered (Cohen et al, 1999).
c) CASE SERIES 1) In a retrospective analysis of 26 patients with olanzapine poisoning, 9 patients (35%) with moderate poisoning (doses ranged from 120 mg to 840 mg) showed unpredictable alternating cycles of somnolence and agitation. Five patients also had marked miosis (Palenzona et al, 2004).
2) In a retrospective series of 12 patients with olanzapine overdose, 5 patients were exposed to olanzapine as the sole ingestant and 7 patients were exposed to olanzapine with other coingestants. Four of the 5 patients (including a 3-year-old child) who had ingested olanzapine alone developed lethargy. In 3 of the 4 cases, the lethargy persisted for longer than 8 hours (Powell et al, 1997). The ingested dose range of olanzapine was 25 to 135 mg.
d) CASE REPORTS 1) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
2) A 39-year-old woman with schizophrenia who ingested 100 mg of olanzapine, presented to an ED after gastric lavage and activated charcoal treatment in a referring hospital. On presentation, she had an arterial blood pressure of 110/70 mm Hg, a heart rate of 90 beats/min, and a Glasgow Coma Scale (GCS) score of 10. An ECG showed normal sinus rhythm. Approximately 8 hours after she was transferred to the ICU, her GCS decreased to 7 and she was treated with 100 mL of 20% lipid emulsion infused over 15 minutes. During the lipid infusion, her respiratory rate gradually decreased from 24 to 14. After the infusion, her GCS increased to 15 and she became arousable with a mild agitation. About 10 hours later, her GCS decreased again to 11 and she gradually recovered after receiving 100 mL of 20% lipid emulsion infused over 30 minutes (Yurtlu et al, 2012).
3) A 4-year-old boy with a history of an untreated seizure disorder developed tachycardia (170 beats/min) and agitation, followed by somnolence and minimal response to painful stimuli after ingesting an unknown quantity of olanzapine. He was treated with 20% lipid emulsion (a 1.5 mL/kg lipid emulsion bolus, followed by a 0.25 mL/kg/min infusion) starting approximately 90 minutes after presentation. His heart rate decreased to 115 to 120 beats/min within 15 minutes of the initial bolus and he became more arousable. During the transfer to the ICU, the lipid emulsion infusion was inadvertently discontinued for 45 minutes and his heart rate increased to 180 to 190 beats/min. Once again, the patient was treated with an additional lipid emulsion bolus of 1.5 mL/kg, followed by the lipid infusion. He gradually recovered and was discharged 2 days later (McAllister et al, 2011).
4) A 2.5-year-old boy was sleepy but arousable 10 hours after an estimated ingestion of 15 mg olanzapine. The patient recovered following supportive therapy (Yip et al, 1998).
5) Two patients were found unresponsive following olanzapine overdose. One patient was a 56-year-old woman who had also supposedly ingested amitriptyline, lorazepam, and divalproex sodium. The other patient was a 15-year-old female who had ingested approximately 115 mg olanzapine as the sole ingestant. Both patients recovered following supportive care (Dougherty et al, 1997).
6) Prolonged CNS depression is reported following ingestion of 10 mg olanzapine in a 17 kg child. After an evening dose (dispensing error), the child was unarousable the next morning. Slurred speech, staggering gait, and extreme drowsiness were apparent 15 hours after the ingestion. The child slept mostly through a 37.5 hour period following the ingestion and slept most of the fifth and sixth days, returning to baseline on day 7 (Bond & Thompson, 1998).
7) Obtundation, with Glasgow Coma Scale of 6 to 7, was reported in a 31-year-old woman approximately 15 hours following the ingestion of up to 600 mg olanzapine (Fogel & Diaz, 1998).
8) Progressive anticholinergic syndrome has been reported in severe olanzapine poisoning. A 25-year-old man suffered progressive delirium, dilated nonreactive pupils, dry skin and mucous membranes, tachycardia, and elevated blood pressure within 3 to 4 hours of ingesting 300 mg olanzapine in a suicide attempt. His sensorium cleared rapidly after he received a total of 3 mg physostigmine over about 15 minutes (Mazzola et al, 2003).
9) CASE REPORT: A 17-month-old toddler (weight: 12.8 kg) was found lethargic and drowsy by her parents after ingesting 2 to 5 olanzapine 10 mg tablets. On presentation, she was agitated, but all laboratory results were normal. Her serum olanzapine concentration was 439 nmole/L (137 ng/mL; therapeutic range: 32 to 256 nmole/L; 10 to 78 ng/mL) 24 hours after olanzapine ingestion. At this time, she developed severe and prolonged extrapyramidal symptoms (eg, ataxia, tremor) that lasted until 5 days after admission (6 days postingestion). In addition, she had fever (38 to 39 degrees C) for 3 days. Her symptoms gradually improved following supportive care and she was discharged on day 7 (Tanoshima et al, 2013).
B) EXTRAPYRAMIDAL DISEASE 1) WITH THERAPEUTIC USE a) Extrapyramidal effects have occurred in clinical trials and appear to be dose-related (>20 mg/day) (Bronson & Lindenmayer, 2000). Hypertonia and akathisia have been reported in less than 9% of treated patients, with parkinsonian tremor occurring in approximately 5% (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Beasley et al, 1996; Anon, 1994). Tardive dyskinesia is possible with olanzapine use (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007). The elderly appear to be more sensitive to extrapyramidal side effects of olanzapine (Granger & Hanger, 1999).
b) In a comparative trial, akathisia, tremor, and dystonia were reported in 16%, 15%, and 13% of schizophrenic patients, respectively, receiving haloperidol (mean, 16 mg daily). Corresponding incidences in those treated with olanzapine in higher doses (mean, 16 mg daily) were 7%, 6%, and 0% (Beasley et al, 1996).
c) CASE REPORT: A 73-year-old woman treated with olanzapine 30 mg daily for bipolar disorder developed drug-induced parkinsonism after smoking cessation (40 packs/year). Despite treatment with carbidopa-levodopa (discontinued 1 week prior to admission) for suspected Parkinson disease, she was hospitalized for altered mental status, weakness, and ambulatory dysfunction 4 months after smoking cessation. A monthlong cross-taper to discontinue olanzapine and initiate aripiprazole was started and she was discharged after 11 days with no evidence of parkinsonism (Arnoldi & Repking, 2011).
d) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Twenty-five patients (27%) developed extrapyramidal symptoms with suspected causal relation to olanzapine (doses used: 50 to 120 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) Although uncommon, large overdoses may result in extrapyramidal effects appearing as spastic movements, tremor, trismus, fasciculations, cogwheel rigidity, oculogyric crisis and/or dystonia(Theisen et al, 2005; Shrestha et al, 2001; Chambers et al, 1998; Fogel & Diaz, 1998) .
b) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
c) CASE REPORT: Tremor, persisting for 2 days, is reported in a 17 kg child following an accidental ingestion of 10 mg olanzapine (Bond & Thompson, 1998).
d) CASE REPORT: Rigidity on passive motor examination, fasciculations in the arms, and a clenched jaw were reported in a 31-year-old woman about 15 hours following ingestion of up to 600 mg olanzapine (Fogel & Diaz, 1998).
e) CASE REPORT: Acute extrapyramidal symptoms, occurring 36 hours after ingestion, were seen in a 9-year-old boy following an overdose of 100 mg olanzapine and acetaminophen in a suicide attempt. Hyperreflexia followed by tremors of the extremities, cogwheel rigidity, trismus, oculogyric signs, and severe dystonia of the neck were reported. Symptoms improved following treatment with intravenous diphenhydramine (Chambers et al, 1998).
f) CASE REPORTS: Shrestha et al (2001) reported 2 patients with extrapyramidal movements following large olanzapine overdoses. The first patient exhibited extraocular movements including involuntary nystagmus/oculogyric crisis. Involuntary limb twitching was noted. The second patient exhibited total body spasms for 1 to 2 seconds following a simple nudge. Both patients recovered (Shrestha et al, 2001).
g) CASE REPORT: A 62-year-old man presented to the ED with confusion, restlessness, and lethargy after intentionally ingesting 50 olanzapine 15 mg tablets. A neurologic exam showed hyperactive reflexes and limb ataxia. During his hospitalization, the patient became semicomatose and developed hypersalivation and frequent persistent choreoathetosis with dystonia of his head and all extremities. An MRI revealed small hyperintense foci in the medial putaminis globus pallida and left caudate head. Late complications, including pneumonia, sepsis, and skin infections, resulted in the patient's death approximately 57 days postingestion (Davis et al, 2005).
h) CASE REPORT: A 17-month-old toddler (weight: 12.8 kg) was found lethargic and drowsy by her parents after ingesting 2 to 5 olanzapine 10 mg tablets. On presentation, she was agitated, but all laboratory results were normal. Her serum olanzapine concentration was 439 nmole/L (137 ng/mL; therapeutic range: 32 to 256 nmole/L; 10 to 78 ng/mL) 24 hours after olanzapine ingestion. At this time, she developed severe and prolonged extrapyramidal symptoms (eg, ataxia, tremor) that lasted until 5 days after admission (6 days postingestion). In addition, she had fever (38 to 39 degrees C) for 3 days. Her symptoms gradually improved following supportive care and she was discharged on day 7 (Tanoshima et al, 2013).
C) LARYNGEAL DYSTONIA 1) WITH THERAPEUTIC USE a) Laryngeal dystonia has been reported in a patient after receiving IM olanzapine (Olives et al, 2015). 1) CASE REPORT: A 32-year-old man presented to the ED after ingesting 12 hydrocodone/acetaminophen tablets and received several doses of IV naloxone. During questioning about his intentional self-harm, he became agitated and was treated with 10 mg of IM olanzapine. About 7 minutes later, he became hypoxic and unresponsive, with a left-deviated gaze and absent chest rise, and his SpO2 decreased to the mid-70% range. Following aggressive supportive therapy and emergent airway maneuvers, including jaw thrust, aggressive bag-valve-mask (BVM) ventilation, and neuromuscular paralysis with intubation, his symptoms gradually improved and he was discharged on day 2 after psychiatric evaluation (Olives et al, 2015).
D) SEIZURE 1) WITH THERAPEUTIC USE a) Seizures have been reported with therapeutic use. Patients with histories of seizures or conditions that lower the seizure threshold may be more prone to seizures following olanzapine therapy or overdose (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Lee et al, 1999). 1) Drug interactions with other drugs that lower the seizure threshold, such as clomipramine, have been reported to result in seizures with concomitant olanzapine (Deshauer et al, 2000).
b) Fatal status epilepticus associated with olanzapine therapy in a woman with no underlying cause or predisposing factors for seizure has been reported. She had been on olanzapine therapy for 5 months prior to the seizures. Subsequent to the seizures she died from secondary rhabdomyolysis and disseminated intravascular coagulation. The authors classified this as a probable adverse event due to olanzapine (Wyderski et al, 1999). 2) WITH POISONING/EXPOSURE a) Seizures have been reported in only 0.9% of patients in premarketing clinical trials. Patients with histories of seizures or conditions that lower the seizure threshold may be more prone to seizures following olanzapine therapy or overdose (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Lee et al, 1999) .
b) CASE REPORT: A 62-year-old man, who intentionally ingested 50 olanzapine 15 mg tablets, developed periods of coarse horizontal nystagmus that became continuous over time. An EEG showed frequent small amplitude spike and wave complexes occurring predominantly in the frontocentral temporal and anterior temporal regions. Because the patient exhibited no limb movement, a diagnosis of nonconvulsive status epilepticus was made. His nystagmus slowly resolved following administration of valproate (Davis et al, 2005).
c) CASE REPORT: A 32-year-old man with a 12-year history of schizophrenia, paranoid subtype developed seizures (2 partial complex seizures involving his left upper extremity) and coma after taking 70 olanzapine 10 mg tablets (700 mg). The patient recovered after supportive therapy (Bhanji et al, 2005).
E) PSYCHOMOTOR AGITATION 1) WITH THERAPEUTIC USE a) Agitation has been reported in up to 23% of olanzapine treated patients in clinical trials, as compared with 17% taking placebos. Agitation, insomnia, and nervousness may be a part of the disease process as opposed to a pharmacologic effect of the drug (Prod Info Zyprexa(R), olanzapine, 1996).
2) WITH POISONING/EXPOSURE a) Overdoses have resulted in agitation and tachycardia (Yurtlu et al, 2012; McAllister et al, 2011; Bonin & Burkhart, 1999; Gardner et al, 1999) followed by prolonged lethargy.
b) CASE REPORT: A 4-year-old boy with a history of an untreated seizure disorder developed tachycardia (170 beats/min) and agitation, followed by somnolence and minimal response to painful stimuli after ingesting an unknown quantity of olanzapine. He was treated with 20% lipid emulsion (a 1.5 mL/kg lipid emulsion bolus, followed by a 0.25 mL/kg/min infusion) starting approximately 90 minutes after presentation. His heart rate decreased to 115 to 120 beats/min within 15 minutes of the initial bolus and he became more arousable. During the transfer to the ICU, the lipid emulsion infusion was inadvertently discontinued for 45 minutes and his heart rate increased to 180 to 190 beats/min. Once again, the patient was treated with an additional lipid emulsion bolus of 1.5 mL/kg, followed by the lipid infusion. He gradually recovered and was discharged 2 days later (McAllister et al, 2011).
c) In a retrospective analysis of 26 patients with olanzapine poisoning, 9 patients (35%) with moderate poisoning (doses ranged from 120 mg to 840 mg) showed unpredictable alternating cycles of somnolence and agitation. Five patients also had marked miosis (Palenzona et al, 2004).
d) CASE REPORT: A 28-month-old girl inadvertently ingested 30 mg of olanzapine and became unconscious within 6 hours of ingestion. Tachycardia and unresponsive, restricted pupils were noted upon arrival. Six hours after admission to the pediatric ICU, she regained consciousness with supportive therapy. Upon regaining consciousness she was agitated, her speech was slurred, and her movements were uncoordinated. Thirty-six hours after admission she had full recovery (Lankheet et al, 2011).
e) CASE REPORT (CHILD): A 2.5-year-old boy was agitated, irritable, and hostile 10 hours after an accidental ingestion of an estimated 15 mg olanzapine. The patient recovered following supportive care (Yip et al, 1998).
F) NEUROLEPTIC MALIGNANT SYNDROME 1) WITH THERAPEUTIC USE a) Neuroleptic malignant syndrome (NMS), due to dopaminergic blockade, associated with olanzapine therapy has been reported, but is rare. Patients taking concomitant or recently discontinued neuroleptics appear to be more susceptible to drug-induced NMS. CK serum levels are usually elevated; urine myoglobin levels may be elevated; and high fever and rigidity are present. Generally after stopping the drug therapy and administering supportive therapies, NMS resolves (Nyfort-Hansen & Alderman, 2000; Sierra-Biddle et al, 2000; Stanfield & Privette, 2000; Cohen et al, 1999; Filice et al, 1998; Moltz & Coeytaux, 1998) .
b) CASE REPORT/STABLE THERAPY: An 82-year-old woman with a history of dementia, depression, and hypertension and on stable doses of quinapril/hydrochlorothiazide, citalopram, donepezil, benserazide-levodopa and olanzapine, was admitted with a 12 hour history of stupor and fever. Her physical exam included severe muscle rigidity that affected all extremities, aphasia, Babinski's and Hoffman's signs of both legs and a GCS of 7. Her temperature continued to rise over several days and on day 4 her temperature peaked at 41.3 degrees C and her CK peaked at 1826 Units/L. All previous medications, including olanzapine, were withdrawn. On day 7, dantrolene was started due to ongoing fever, elevated BP, generalized muscular rigidity and elevated CK levels. Improvement was noted within 24 hours and on hospital day 10 the patient was afebrile, muscular rigidity had resolved and GCS was 9. The patient was transferred to a rehab center, but her GCS did not improve any further and she died from a cardiac arrest 15 days later (Kouparanis et al, 2015).
c) CASE REPORT/FATALITY: A 52-year-old man with a new onset of stress-induced mood disturbance was prescribed olanzapine and developed an altered mental status, rigidity, diaphoresis, urinary incontinence, and a high temperature after ingesting a single 5 mg dose. Approximately 24 hours after ingestion, the patient was admitted with a Glasgow Coma Scale score of 6, lead-pipe rigidity, generalized myoclonus and a serum CPK concentration of 8240 Units/L (normal: 60 to 400 Units/L), and myoglobinuria. Neuroleptic malignant syndrome was diagnosed and the patient was treated with bromocriptine and clonazepam. Over the next week the CPK normalized, but there was minimal clinical improvement of CNS function. The patient developed complications due to immobility and died of aspiration pneumonia 8 weeks after exposure (Majumder et al, 2009).
d) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Two patients (2%) developed neuroleptic malignant syndrome with suspected causal relation to olanzapine (doses used: 50 to 90 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 36-year-old woman with a history of schizophrenia presented to an emergency department 4 hours after ingesting 30 olanzapine 10 mg tablets, 7 chlorpromazine 100 mg tablets, and an unknown amount of escitalopram. The patient recovered within 24 hours from her initial acute exposure. However, on day 3 the patient was noted to be confused with symptoms of incontinence. Neurological exam revealed generalized hyperreflexia and ataxia. Laboratory analysis showed an increase in white blood cell count and serum creatinine (previously normal). Despite treatment with bromocriptine, the patient continued to deteriorate neurologically and was febrile. Midazolam and external cooling were added. By day 6, elective intubation was performed for ongoing neurological insufficiency. Clinical improvement was noted on day 10 and the patient was extubated the following day. The patient recovered within 3 weeks with no signs of clinical deterioration; mild confusion was noted for approximately 1 week (Morris et al, 2009). The combined antagonism of dopamine receptors by chlorpromazine and olanzapine likely contributed to the development of NMS in this patient.
G) SEROTONIN SYNDROME 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 35-year-old man was found collapsed after ingesting olanzapine 840 mg and paracetamol 2.5 g, and within 12 hours had a creatine kinase level of 11781 U/L. He developed slurred speech, tachycardia, fever, and brisk reflexes with ankle clonus and was diagnosed with serotonin syndrome. Serum olanzapine concentration was 361 mcg/L shortly after admission. Clinical effects resolved within 12 hours, along with a gradual decline of CK measurements over 4 days (Waring et al, 2006).
b) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
H) ALTERED MENTAL STATUS 1) WITH POISONING/EXPOSURE a) CASE REPORTS: A 25-year-old man became agitated, delirious, had dry skin and mucous membranes, and developed dilated pupils (6 mm) that were minimally reactive to light 2 hours after ingesting 300 mg olanzapine. He was treated with 0.5 mg IV physostigmine without any effects. Five minutes later, he was given another 1.5 mg with gradual improvement in his delirium. Another 1 mg was given resulting in a clear sensorium and normal mentation. 1) A 20-year-old woman who ingested 600 mg olanzapine presented with tachycardia was obtunded and minimally responsive to painful stimuli. She was given 2 mg physostigmine IV and regained full consciousness. After 30 minutes she again became obtunded. Serum olanzapine level was 1230 ng/mL. No additional physostigmine was given and her mental status returned to normal on day 3 of admission (Weizberg et al, 2006).
2) A 53-year-old man who had taken an overdose of 260 mg of olanzapine presented with a Glasgow Coma Scale score of 5. He was unresponsive, with pinpoint pupils and bilateral upgoing plantar reflexes, increased tone throughout, and brisk reflexes. He was intubated and observed overnight. The following day he was extubated, his neurologic exam had normalized, he had equally reactive pupils and downgoing plantars (Broyd & McGuinness, 2006).
I) AKATHISIA 1) WITH THERAPEUTIC USE a) CASE REPORTS: Two patients were diagnosed with akathisia after being treated with olanzapine 10 mg/day. Both were successfully treated with mirtazapine 15 mg/day. In 1 patient, mirtazapine was tapered and stopped after 4 weeks and he was maintained on olanzapine 7.5 mg/day without relapse of the akathisia. In the second patient, the akathisia improved after 3 days of treatment, her depression disappeared and she was continued on olanzapine 10 mg/day and mirtazapine 15 mg/day. 1) A third patient who was receiving escitalopram 20 mg/day and lamotrigine 100 mg/day for bipolar depression and psychotic symptoms developed akathisia after olanzapine 7.5 mg/day was added for treatment of psychotic symptoms. The patient was started on mirtazapine 15 mg/day and improvement in her symptoms was observed after 1 week of treatment (Ranjan et al, 2006).
J) DELIRIUM 1) WITH THERAPEUTIC USE a) Post-injection olanzapine delirium/sedation syndrome (PDSS) has been reported in several patients after receiving olanzapine long-acting IM injection (OLAI). Symptoms of PDSS are similar to those of acute oral olanzapine overdose. It is suggested that PDSS may occur after an accidental intravascular entry of olanzapine from a vessel injury during the injection. In addition, olanzapine pamoate salt dissolves more rapidly in blood than in muscle tissue, resulting in the rapid rate of drug release and very high olanzapine concentrations. Patients with low BMI and/or higher age may have a higher risk in developing PDSS (Lukasik-Glebocka et al, 2015). 1) CASE REPORT: Post-injection olanzapine delirium/sedation syndrome (PDSS) developed in a 60-year-old schizophrenic woman (BMI 18.2 kg/m[2]) 10 minutes after receiving her fourth IM injection of olanzapine pamoate (dose, 405 mg every 4 weeks). She presented unconscious with bilateral miosis, occasional agitation, and slight rigidity. Vital signs included a blood pressure of 140/75 mmHg, heart rate of 112 to 130 beats/min, and a respiratory rate of 16 breaths/min. Her body temperature also increased from 36.6 degrees C to 38.2 degrees C during the first 5 hours. Following supportive care, including treatment with midazolam for agitation and biperiden for rigidity, her symptoms gradually improved and she was fully conscious 48 hours after the injection. Laboratory results revealed serum olanzapine concentrations of 698, 530, 544, and 271 ng/mL at 5, 14, 24, and 48 hours after injection (recommended therapeutic concentration: 20 to 80 ng/mL), respectively (Lukasik-Glebocka et al, 2015).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTROENTERITIS 1) WITH THERAPEUTIC USE a) Nausea, vomiting, dry mouth, constipation, dyspepsia have been reported with therapeutic use. Dysphagia has also occurred (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007) .
B) PARASYMPATHOLYTIC POISONING 1) WITH THERAPEUTIC USE a) Anticholinergic effects, consisting of decreased bowel sounds, constipation and dry mouth, are common adverse effects of olanzapine therapy. These effects are dose-related (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Isbister et al, 2001; Beasley et al, 1996; Fogel & Diaz, 1998).
2) WITH POISONING/EXPOSURE a) Anticholinergic effects, consisting of decreased bowel sounds, constipation, and dry mouth are common adverse effects of olanzapine therapy. These effects are dose-related and may be anticipated following overdose (Mazzola et al, 2003; Isbister et al, 2001; Fogel & Diaz, 1998; Beasley et al, 1996) . Decreased gastrointestinal motility was reported in a pediatric overdose (Chambers et al, 1998), and was treated with promotility drugs, including cisapride, ondansetron, and metoclopramide.
C) PANCREATITIS 1) WITH THERAPEUTIC USE a) A probable adverse event of olanzapine-induced acute hemorrhagic pancreatitis has been reported. Olanzapine was started 6 days prior to the onset of symptoms. Other concomitant drugs were ruled out as contributing to pancreatitis. Death due to secondary unrelenting peritonitis occurred in this case (Doucette et al, 2000). This is considered a rare adverse effect of olanzapine. 1) Woodall & DiGregorio (2001) point out discrepancies in the case above, including the use of multiple medications (ketorolac, acetaminophen, temazepam, verapamil) and chronic alcoholism, which they believe could possibly contribute to acute onset pancreatitis.
D) EXCESSIVE SALIVATION 1) WITH POISONING/EXPOSURE a) Hypersalivation, requiring frequent mouth suctioning, was reported in a 62-year-old man following intentional ingestion of 50 olanzapine 15 mg tablets (Davis et al, 2005).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Elevations of serum aspartate and alanine aminotransferase and gamma-glutamyl transferase (GGT) have been reported following olanzapine therapy in clinical trials. These elevations, which have been significant in 10% of patients, appear to be dose-dependent and are reversible on discontinuation of the drug (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Bronson & Lindenmayer, 2000; Beasley et al, 1996) .
b) CASE REPORT: A 78-year-old woman was prescribed olanzapine 10 mg/day for acute depression with psychotic features. Thirteen days later, she was admitted to the hospital for fever associated with nausea, upper abdominal pain, arthralgia, and malaise. On admission liver function tests showed elevated aspartate aminotransferase (361 Units/L), alanine aminotransferase (204 Units/L), total bilirubin (22 mmol/L), and alkaline phosphatase (189 Units/L). On hospital day 4, the patient's symptoms resolved. The patient was asymptomatic and results of liver function tests had normalized at follow-up 4 weeks later (Jadallah et al, 2003).
c) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. One patient developed elevated liver enzymes with suspected causal relation to olanzapine (doses used: 60 mg) (Petersen et al, 2014).
B) INFLAMMATORY DISEASE OF LIVER 1) WITH THERAPEUTIC USE a) In the postmarketing period, there have been rare reports of hepatitis and cholestatic or mixed liver injury (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) PRIAPISM 1) WITH POISONING/EXPOSURE a) Priapism may occur rarely following an overdose of atypical neuroleptics, including olanzapine. It is suggested that alpha-2 blockade may exacerbate alpha-1 mediated priapism potential by stimulating release of nitric oxide from neurons innervating afferent arterioles and the corpora cavernosa. Olanzapine has alpha-1 and alpha-2 blocking characteristics, which may contribute to priapism (Matthews & Dimsdale, 2001).
b) CASE REPORT: Following an intentional overdose of olanzapine (100 mg) and gabapentin (1500 mg), a 51-year-old man was admitted to the hospital. Within 19 hours of the ingestion, a painful ischemic priapism was diagnosed. After 2 lidocaine injections and an intracorporeal shunt was placed, the patient recovered (Matthews & Dimsdale, 2001).
B) DIABETES INSIPIDUS 1) WITH POISONING/EXPOSURE a) CASE REPORT: After taking 15 tablets (75 mg) of olanzapine and 7.5 mg of prazepam in a suicide attempt, a 17-year-old boy developed central diabetes insipidus (polyuria [5400 mL/24 hours]; hyposmolar urine [166 mosmol/kg H2O]; normosmolar plasma [287 mosmol/kg H2O]; increased serum sodium level [increasing from 132mmol/L on admission to 141 mmol/L when polyuric]). Other laboratory results: blood ADH level 3.1 pg/mL (normal range 0.0 to 8.0); TSH level of 6.01 mcUnits/mL (normal range 0.2 to 3.5). Following treatment with desmopressin, he recovered without further sequelae (Etienne et al, 2004).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) AGRANULOCYTOSIS 1) WITH THERAPEUTIC USE a) Unlike clozapine, a structurally related drug, olanzapine has not been shown in preclinical trials to cause any significant leukopenia or agranulocytosis; however, it has been shown to rarely cause agranulocytosis in isolated case reports postmarketing Tolosa-Vilella et al, 2001; (Beasley et al, 1996) Anon, 1995; (Anon, 1994) . Due to the similarities of the 2 drugs, there may be a potential for abnormal hematologic reactions. Several cases of olanzapine adversely prolonging the recovery time of clozapine-induced granulocytopenia have been reported (Konakanchi et al, 2000).
b) CASE REPORT: Following clozapine-induced neutropenia in an adult, clozapine was discontinued. Five days later neutrophil count normalized. Olanzapine was then introduced. After 1 week neutrophil count dropped and olanzapine was stopped. After 4 weeks, neutrophil count again normalized (Benedetti et al, 1999).
c) CASE REPORT: A case of olanzapine-induced agranulocytosis, after clozapine therapy, was reported in a 27-year-old man. On the ninth day of therapy his total white cell count decreased from 5.8 x 10(9)/L to 3.4 x 10(9)/L but with a normal neutrophil count. Olanzapine was discontinued. One day later the leukocyte and neutrophil count both dropped. Three days after stopping the drug the neutrophil count was still dropping. Following therapy with G-CSF his condition improved (Naumann et al, 1999).
d) CASE REPORT: Fifteen days after starting olanzapine (5 mg/day), a 46-year-old man presented to the hospital with fever, chills, and odynophagia. He was also concurrently taking cyanamide. A white blood cell count of 0.5 x 10(9)/L with a neutrophil count of 0.36 x 10(9)/L was noted. Olanzapine and cyanamide were stopped and antibiotic therapy was initiated. By the sixth hospital day, his white blood cell had normalized. A temporal relationship between olanzapine therapy and new onset agranulocytosis was noted (Tolosa-Vilella et al, 2002).
B) LEUKOCYTOSIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) DRY SKIN 1) WITH POISONING/EXPOSURE a) Dry skin, an anticholinergic type effect, may occur following overdoses (Mazzola et al, 2003; Fogel & Diaz, 1998).
B) ERUPTION 1) WITH POISONING/EXPOSURE a) CASE REPORT: A bumpy, pruritic rash was noted on the trunk and legs of a 17 kg child on the second day following an accidental ingestion of 10 mg of olanzapine. The rash responded to treatment with triamcinolone cream (Bond & Thompson, 1998).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) JOINT PAIN 1) WITH THERAPEUTIC USE a) Joint pain, extremity pain (other than joint), and twitching have been reported with therapeutic use. Asymptomatic elevations in creatine phosphokinase (CPK) have also been reported (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007).
B) INCREASED CREATINE KINASE LEVEL 1) WITH THERAPEUTIC USE a) Marked elevation of serum creatine kinase (CK) associated with olanzapine therapy, with no other diagnostic criteria for neuroleptic malignant syndrome, has been reported. No psychomotor agitation was present. Drug discontinuation resulted in return to baseline of serum CK (Marcus et al, 1999).
b) CASE REPORT/PEDIATRIC: A 16-year-old boy with a long history of severe conduct disorder and aggression was started on risperiDONE with partial improvement of disruptive behavior. However, he developed extrapyramidal side effects and the drug was discontinued. Olanzapine was started and titrated to 10 mg/day. During a routine laboratory study, his serum creatine kinase (CK) level was 543 Units/L (peaked at 10,350 Units/L 20 days later). Other elevated laboratory studies included AST 115 Units/L (range up to 40) and LDH 394 Units/L (range, 135 to 225). The patient's physical and neurologic exam remained normal along with a normal ECG and QTc. Olanzapine was discontinued and within a week his CK dropped significantly and was normal within 15 days. Olanzapine was initially restarted at 5 mg/day and his CK level began to rise again with no symptoms. Eventually, the patient was stabilized using olanzapine 7.5 mg/day with improvement in disruptive behavior and normal laboratory findings (Masi et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 16-year-old boy presented unconscious (Glasgow Coma Scale score 7) about 10 hours after ingesting 750 mg of olanzapine. On presentation, he was tachycardic and hypotensive and had generalized myoclonus, fever and muscular rigidity. Laboratory results showed leukocytosis and elevated CPK levels. Following supportive care, all symptoms, except for tachycardia, resolved by day 4. His pulse rate resolved on day 8 and he was discharged home (Singh et al, 2012).
b) CASE SERIES: In a retrospective review of 64 patients admitted for acute olanzapine exposure, 17% (n=11) of patients had creatine kinase values of greater than 500 units/L. Regression analysis showed a close correlation between the quantity of olanzapine ingested and the creatine kinase level. An increase in muscle toxicity was observed with higher doses of olanzapine, suggesting a dose-dependent effect. A delay of 12 hours was also found before a maximum CK value was reached. Coingestants were reported in 46 (72%) patients with antidepressants and benzodiazepines being the 2 most commonly reported drugs. None of these patients developed renal failure (Waring et al, 2006).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPERPROLACTINEMIA 1) WITH THERAPEUTIC USE a) Dose-related increases in serum prolactin levels have been reported following olanzapine therapy. Serum prolactin elevations in clinical trials have been small (about 0.1 to 0.2 nmol/L) (Prod Info ZYPREXA(R) oral tablets, orally disintegrating tablets, IM injection, 2007; Beasley et al, 1996).
b) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Eight patients (9%) developed hyperprolactinemia/gynecomastia with suspected causal relation to olanzapine (doses used: 50 to 70 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 17-month-old toddler (weight: 12.8 kg) was found lethargic and drowsy by her parents after ingesting 2 to 5 olanzapine 10 mg tablets. On presentation, she was agitated, but all laboratory results were normal. Her serum olanzapine concentration was 439 nmole/L (137 ng/mL; therapeutic range: 32 to 256 nmole/L; 10 to 78 ng/mL) 24 hours after olanzapine ingestion. At this time, she developed severe and prolonged extrapyramidal symptoms (eg, ataxia, tremor) that lasted until 5 days after admission (6 days postingestion). In addition, she had fever (38 to 39 degrees C) for 3 days. Her symptoms gradually improved following supportive care and she was discharged on day 7. Serum prolactin concentrations were 16.7 mcg/L and 13.3 mcg/L on day 2 and day 5 (reference range of age 1 year to puberty: 3 to 15 mcg/L), respectively (Tanoshima et al, 2013).
B) HYPERGLYCEMIA 1) WITH THERAPEUTIC USE a) Olanzapine-induced glucose dysregulation has been reported as an adverse effect. Contributing factors may include damage to the pancreatic islet cells, weight gain, dysregulation of the sympathetic system, and insulin resistance. New onset diabetes mellitus (DM) and diabetic ketoacidosis have been reported with the administration of olanzapine (Bechara & Goldman-Levine, 2001; Bonanno et al, 2001; Koller et al, 2001; Ragucci & Wells, 2001; Roefaro & Mukherjee, 2001; Seaburg et al, 2001; Van Meter et al, 2001) . In one case, a patient developed severe exacerbation of type 2 diabetes mellitus following the initiation of olanzapine therapy (Bettinger et al, 2000).
b) CASE REPORT: Diabetic ketoacidosis following 3 months of olanzapine therapy was reported in a 31-year-old man with no familial or personal history of diabetes. The patient was started on insulin and olanzapine was discontinued. Fifteen days later his insulin requirements decreased and then stopped. Eight months later the patient had remained metabolically stable, free of diabetic symptoms (Gatta et al, 1999).
c) HIGH-DOSE THERAPY: An observational case series (n=91) examined the incidence of adverse effects associated with high-dose olanzapine therapy (doses: greater than 40 mg daily) in inpatient psychiatric units in Denmark. Olanzapine (dose range: 5 to 80 mg daily) was used by about 50% of patients before admission. All patients were treated with maximum olanzapine daily doses of 45 to 160 mg during admission. Other antipsychotic agents were also used by half of the patients. Two patients (2%) developed diabetes/worsening of diabetes with suspected causal relation to olanzapine (doses used: 60 to 70 mg) (Petersen et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 58-year-old woman with a history of schizophrenia was found unconscious after ingesting 560 mg of olanzapine. At 10 hours, she developed an elevated blood sugar of 350 mg/dL and was given a total of 22 units of short acting insulin. Her blood glucose decreased to 213 mg/dL at 20 hours, and to 113 to 140 m/dL at 25 hours. No permanent sequelae was reported (Ballesteros et al, 2007).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) CELL-MEDIATED IMMUNE REACTION 1) WITH THERAPEUTIC USE a) CASE REPORT: Olanzapine-induced hypersensitivity syndrome, consisting of fever, rash, eosinophilia, and toxic hepatitis, has been reported in a 34-year-old man 60 days after initiation of olanzapine therapy. Symptoms resolved following the discontinuation of olanzapine. Skin and liver biopsies confirmed drug-induced hypersensitivity syndrome (Raz et al, 2001).
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Reproductive |
3.20.1) SUMMARY
A) Olanzapine is classified as FDA pregnancy category C. Fluoxetine/olanzapine combination is classified by the manufacturer as FDA pregnancy category C. Limited human data have shown slight increases in the incidence of major malformations, spontaneous and therapeutic abortions, stillbirths, or premature deliveries. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Teratogenicity has not been observed in rat and rabbit reproduction studies; however, early resorptions, increased numbers of nonviable fetuses, and fetal toxicity have been observed. Limited data from studies of nursing mothers treated with olanzapine have demonstrated that olanzapine is excreted into human breast milk. In rat studies, fertility impairment and mating performance impairment have been reported in females and males, respectively.
3.20.2) TERATOGENICITY
A) CARDIOVASCULAR DEFECT 1) During clinical trials, 1 of the 7 reported olanzapine-exposed pregnancies resulted in neonatal death due to a cardiovascular defect (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010).
B) CONGENITAL MALFORMATIONS 1) A systematic review of the literature found no significant correlation between first-trimester exposure to olanzapine and risk of congenital malformations. However, of 1090 pregnancies with first-trimester exposure, 38 malformations were observed, resulting in a malformation rate of 3.5%. In addition, among 8 children there were 3 case reports of malformations following olanzapine (10 to 15 mg/day) exposure during the first-trimester. The cases included an infant with developmental hip dysplasia diagnosed 3 months after birth (not a true malformation), another with ankyloblepharon and meningocele, and a third was born with unilateral clubfoot and an atrioventricular canal defect (Ennis & Damkier, 2015).
2) In an analysis of expanded data from a prospective study that included 96 olanzapine-exposed pregnancies, major malformation were reported in 1% of the pregnancies (Ernst & Goldberg, 2002).
3) CASE REPORT: An infant exposed in utero to olanzapine (maternal dose 5 mg/day) was born with cardiomegaly, jaundice, somnolence, and a heart murmur. However, jaundice and sedation continued despite the initiation of bottle-feeding on day seven of life (Goldstein et al, 2000a).
C) LACK OF EFFECT 1) Four pregnancies were reported during clinical trials of olanzapine pamoate, resulting in 1 normal birth and 3 therapeutic abortions (Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
2) In a prospective study of 23 olanzapine-exposed pregnancies, there were no major malformations reported (Goldstein et al, 2000).
D) ANIMAL STUDIES 1) Administration of olanzapine pamoate intramuscular injection 75 mg/kg (1 and 2 times the maximum recommended human dose of 300 mg every 2 weeks, respectively, on a mg/m(2) basis) in rats and rabbits did not result in teratogenicity or embryo-fetal toxicity (Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
2) In rat and rabbit reproduction studies, there was no evidence of teratogenicity when olanzapine doses of 9 and 30 times the recommended human daily dose were administered to rats and rabbits, respectively (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified olanzapine as FDA pregnancy category C (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010).
2) The manufacturer has classified olanzapine pamoate as FDA pregnancy category C (Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
3) Fluoxetine/olanzapine combination is classified by the manufacturer as FDA pregnancy category C (Prod Info SYMBYAX oral capsules, 2011).
B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS 1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010).
C) FETAL/NEONATAL ADVERSE EFFECTS 1) In 3 separate case reports, serious fetal complications were reported in infants exposed to olanzapine (up to 20 mg/day) throughout pregnancy in women that developed gestational diabetes mellitus. In the first case, the infant was stillborn after premature rupture of the membranes. In the second case, adverse effects included preterm birth, neonatal respiratory distress and hypoglycemia. In the third case, a patient diagnosed with bipolar disorder had a pregnancy outcome resulting in transient, self-remitted neonatal respiratory distress. However, the patient's gestational diabetes mellitus resolved after parturition and she no longer required insulin and the postpartum period was unremarkable (Gentile, 2014).
D) PLACENTAL BARRIER 1) A prospective, observational study of 54 women (mean age, 30.7 years), recruited from the Emory Women’s Mental Health program, exposed to antipsychotic medication during pregnancy, showed permeability of the placental barrier. Outcomes were determined by maternal and umbilical cord blood samples taken at delivery and through data collected from maternal reports and medical records. Placental passage ratios (defined as the ratio of umbilical cord to maternal plasma concentrations) showed a significant difference between antipsychotic medications, with olanzapine 72.1% (95% confidence interval (CI), 46.8% to 97.5%) being the highest, followed by haloperidol 65.5% (95% CI, 40.3% to 90.7%), risperidone 49.2% (95% CI, 13.6% to 84.8%), and quetiapine 24.1% (95% CI, 18.7% to 29.5%) showing the lowest placental passage ratio. There was a greater frequency of preterm deliveries (21.4%, p = less than 0.23), low birth weights (30.8%, p = less than 0.07), and neonatal intensive care admission (30.8%, p = less than 0.09) in infants exposed to olanzapine (Newport et al, 2007).
E) SPONTANEOUS ABORTION 1) During clinical trials, 3 of the 7 reported olanzapine-exposed pregnancies resulted in therapeutic abortion and 1 resulted in spontaneous abortion (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010).
2) In a prospective study of 23 olanzapine-exposed pregnancies, 3 spontaneous abortions (13%) occurred; however, this was within the range of normal historic control rates (Goldstein et al, 2000). In an analysis of expanded data from the prospective study that included 96 olanzapine-exposed pregnancies, spontaneous abortions were reported in 12.5% of the pregnancies (Ernst & Goldberg, 2002).
3) From an ongoing study to assess the fetal safety of atypical antipsychotics, interim results from 32 exposures to risperidone, olanzapine, or quetiapine included 3 spontaneous abortions and 7 therapeutic abortions (McKenna et al, 2003).
F) STILLBIRTH 1) In a prospective study of 23 olanzapine-exposed pregnancies, 1 stillbirth (5%) occurred; however, this was within the range of normal historic control rates (Goldstein et al, 2000). In an analysis of expanded data from the prospective study that included 96 olanzapine-exposed pregnancies, stillbirths were reported in 3.1% of the pregnancies (Ernst & Goldberg, 2002).
2) From an ongoing study to assess the fetal safety of atypical antipsychotics, interim results from 32 exposures to risperidone, olanzapine, or quetiapine included 2 stillbirths (McKenna et al, 2003).
G) PREMATURE BIRTH 1) In an analysis of expanded data from a prospective study that included 96 olanzapine-exposed pregnancies, premature deliveries were reported in 3.1% of the pregnancies (Ernst & Goldberg, 2002).
H) LACK OF EFFECT 1) CASE REPORT: There was an 11 nanograms (ng)/mL to 34 ng/mL ratio of the measured fetal olanzapine plasma level after delivery compared to the maternal olanzapine plasma level drawn before birth in a mother who had been treated with olanzapine 15 mg during pregnancy. During gestation, the maternal olanzapine plasma levels were between 25 and 34 ng/mL. There was normal fetal development with the only complication being gestational diabetes which was resolved with diet. Delivery was uncomplicated with the birth of a healthy infant who developed normally during the first 6 months (Aichhorn et al, 2008)
2) CASE REPORT: A healthy baby was delivered following maternal use of up to 20 mg of olanzapine and 2 mg of trihexyphenidyl daily from week 23 of gestation until 10 days prior to delivery. The infant showed age-appropriate milestones (Mendhekar et al, 2002).
3) CASE REPORT: A 37-year-old woman with a 7-year history of paranoid schizophrenia gave birth to a healthy infant after being treated with olanzapine 25 mg/day starting at week 8 until week 32 when she discontinued it against medical advice. There were no exacerbations of her psychiatric illness during gestation, labor, or delivery. She had not been taking any medications for the 3 months preceding her pregnancy (Lim, 2001).
4) CASE REPORT: Maternal exposure to olanzapine 10 mg/day from week 18 of pregnancy through delivery did not result in any complications during delivery. The infant showed no abnormal findings at 11 months of age despite suspicious motor development at 7 months of age (Kirchheiner et al, 2000).
I) ANIMAL STUDIES 1) RATS: In a rat teratology study, early resorptions and increased numbers of nonviable fetuses were reported at an oral olanzapine dose of 18 mg/kg/day (9 times the maximum recommended human daily (MRHD) oral dose on a mg/m(2) basis) and prolonged gestation was reported at 10 mg/kg/day (5 times the MRHD). Placental transfer of olanzapine has been observed in rat pups (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
2) RABBITS: In a rabbit teratology study, fetal toxicity (ie, increased resorptions and decreased fetal weight) was reported at a maternally toxic oral olanzapine dose of 30 mg/kg/day (30 times the MRHD) (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) In an oral olanzapine study of healthy, nursing women, olanzapine was excreted in breast milk. The estimated mean infant dose at steady state was 1.8% of the maternal olanzapine dose (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
2) In 7 nursing mothers receiving 5 to 20 mg/day of olanzapine, the median infant dose ingested through breast milk was approximately 1% (Gardiner et al, 2003).
3) In an analysis of milk and plasma samples from 5 nursing mothers treated with olanzapine 2.5 mg to 10 mg daily, milk-to-plasma ratios ranged from 0.2 to 0.84. This compared to a theoretical value of 0.38 that was determined using the known pharmacokinetic parameters of the drug. Based on average milk consumption of 0.15 L/kg/day and assuming 100% bioavailability, relative infant dose was estimated to be 0% to 2.5% of the weight-adjusted maternal dose (Croke et al, 2002).
4) CASE REPORT: Olanzapine was excreted in the breast milk in relatively small amounts with a breast milk/plasma concentration ratio of 0.42 at steady state when breast milk was collected by an electric pump from an olanzapine-treated mother and olanzapine concentrations were measured by gas chromatography (Ambresin et al, 2004).
5) CASE REPORT: An infant exposed in utero to olanzapine (maternal dose 5 mg/day) was born with cardiomegaly, jaundice, somnolence, and a heart murmur. However, jaundice and sedation continued despite the initiation of bottle-feeding on day 7 of life. In the same report, a nursing infant exposed to olanzapine at 2 months of age (maternal dose 10 mg/day) had no adverse effects (Goldstein et al, 2000a).
B) LACK OF EFFECT 1) CASE REPORT: There were undetectable infant olanzapine plasma levels (less than 2 nanograms (ng)/mL) despite maternal steady-state trough levels of 32.8 to 39.5 ng/mL following maternal olanzapine doses of 10 mg daily throughout pregnancy and during breastfeeding (Kirchheiner et al, 2000a).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) MALE RATS: The mating performance, but not the fertility, of male rats was impaired during administration of olanzapine 22.4 mg/kg/day (11 times the maximum recommended human daily dose on a mg/m(2) basis. The impairment of mating performance was reversed with discontinuation of olanzapine administration (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
2) FEMALE RATS: When olanzapine was administered at doses that were 1.5 times the maximum recommended human daily dose (MRHD) on a mg/m2 basis, female rats showed a decrease in fertility. Studies in female rats also indicate that olanzapine may produce a delay in ovulation. At doses that were 2.5 times the MRHD, female rats showed an increased precoital period and a reduced mating index (Prod Info ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, 2010; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential for olanzapine or olanzapine/fluoxetine combination.
3.21.4) ANIMAL STUDIES
A) LACK OF INFORMATION 1) OLANZAPINE/FLUOXETINE a) At the time of this review, the manufacturer reports no carcinogenicity or mutagenicity studies have been conducted with olanzapine/fluoxetine combination in animals (Prod Info SYMBYAX(R) oral capsule, 2009).
B) OLANZAPINE 1) BREAST CARCINOMA a) MICE, RATS: Female mice and rats had significantly increased rates of mammary gland adenomas and adenocarcinomas when exposed to oral olanzapine doses of 2 mg/kg/day or greater for 78 weeks and 4 mg/kg/day or greater for 2 years (0.5 and 2 times the maximum recommended human daily oral dose on a mg/m(2) basis), respectively. Toxicity studies in rats using oral olanzapine 0.25, 1, 4, and 8 mg/kg/day resulted in a 4-fold increase in serum prolactin levels. Additionally, there has been an increased frequency of mammary gland neoplasms in rodents following chronic exposure to other antipsychotic agents; these are believed to be prolactin-mediated neoplasms. The relevance for human risk of prolactin-mediated endocrine tumors is unknown (Prod Info ZYPREXA(R), ZYPREXA ZYDIS(R), ZYPREXA IntraMuscular(R) oral tablets, orally disintegrating tablets, IM injection, 2009; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009; Prod Info SYMBYAX(R) oral capsule, 2009).
2) HEPATIC CARCINOMA a) MICE: An increased incidence of liver hemangiomas and hemangiosarcomas was reported in one mouse study when female mice were exposed to oral olanzapine 8 mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/m(2) basis). These results were not duplicated in another female mouse study at doses 2 to 5 times the maximum recommended human daily dose (Prod Info ZYPREXA(R), ZYPREXA ZYDIS(R), ZYPREXA IntraMuscular(R) oral tablets, orally disintegrating tablets, IM injection, 2009; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009; Prod Info SYMBYAX(R) oral capsule, 2009).
C) LACK OF EFFECT 1) OLANZAPINE a) RATS: The incidence of tumors was not increased when rats were treated with olanzapine extended-release IM injections at monthly doses of 5, 10, and 20 mg/kg in males and 10, 25, and 50 mg/kg in females (0.08 to 0.8 times the maximum recommended human dose of 300 mg every 2 weeks on a mg/m(2) basis) for 2 years. In this study, local injection site reactions resulted in limited dosing (Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009).
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Genotoxicity |
A) OLANZAPINE
1) No evidence of mutagenicity was found in the Ames reverse mutation test, in vivo micronucleus test in mice, chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters (Prod Info ZYPREXA(R), ZYPREXA ZYDIS(R), ZYPREXA IntraMuscular(R) oral tablets, orally disintegrating tablets, IM injection, 2009; Prod Info ZYPREXA RELPREVV extended release IM injectable suspension, 2009; Prod Info SYMBYAX(R) oral capsule, 2009).
B) OLANZAPINE/FLUOXETINE
1) At the time of this review, the manufacturer reports no carcinogenicity or mutagenicity studies have been conducted with olanzapine/fluoxetine combination in animals (Prod Info SYMBYAX(R) oral capsule, 2009).
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